Highlights

• Candida-Klebsiella interactions modulate hyphal morphogenesis
• Ectopic morphogenesis encompasses septation, cell wall remodeling and carbon metabolism
• Candida-Klebsiella co-infections trigger tissue hyperinflammation and compensatory regulation
• Candida-Klebsiella co-infection establishes a host environment facilitating microbial dissemination and tissue pathology
• Candida-Klebsiella interactions enhance fungal virulence potentially impacting the severity of co-infections

Summary

Clinically relevant infections commonly develop within polymicrobial environments where interkingdom interactions shape host responses and disease trajectories. Candida albicans and Klebsiella pneumoniae are critical pathogens that can co-exist in the respiratory tract, yet the consequences of their interaction on fungal physiology, pathogenicity, and disease outcomes remain poorly understood.

Here, we show that K. pneumoniae enhances C. albicans virulence traits, suggesting that co-infections could exacerbate lung disease. Mechanistically, bacterial presence induces fungal hyphal morphogenesis via MAPK-CEK signaling, coupled to metabolic rewiring and alterations in cell wall remodeling and septation, resulting in highly elongated hyphae that escape faster from macrophages.

At the host level, co-infection reprograms macrophages into a non-canonical state characterized by overlapping pro- and anti-inflammatory modules, integrating type I interferon and IL-10 signaling. This response contributes to tissue damage and facilitates fungal persistence, revealing that bacterial-fungal interactions coordinately reprogram pathogen behavior and host immunity, promoting pathogenic synergy.